GVHD is a syndrome observed after allogeneic hematopoietic stem cell transplantation (HSCT) and mediated by immunocompetent donor T lymphocytes reactive against the tissues of the recipient.
Increasingly, HSCT is used to treat hematologic malignancies, and other diseases such as aplastic anemia, solid tumors and autoimmune disorders. HSCT remains a powerful treatment option that offers a true chance for a cure of many diseases. Introducing hematopoietic cells into an immunoablated host with successful marrow engraftment, with maintenance of an antitumor effect (if applicable), and without GVHD is the goal of many investigators. GVHD remains, however, as the primary cause of morbidity and mortality in hematopoietic cell recipients.
GVHD can be acute or chronic. Acute GVHD develops in 35-50% of patients given HLA-identical marrow grafts within the first 100 days of transplantation. The main target organs are skin, liver, and intestinal tract. Approximately one half of the patients with moderately severe to severe disease die, usually from associated infections.
Prevention of acute GVHD by immunosuppressive treatment after grafting, or removal of donor lymphocytes from the marrow inoculum has, as yet, not been uniformly successful. Treatment of established GVHD involves the use of immunosuppressors such as glucocorticosteroids, antithymocyte globulin, cyclosporine, and monoclonal antibodies. However, these approaches increase the risk of engraftment failures, delayed immune reconstitution, viral infections and relapses of the original malignant disease.
Chronic GVHD usually develops 100-500 days after transplantation and affects about 45% of all long-term survivors and it is characterized by symptoms similar to those observed for autoimmune disease. The main target organs are the same as those of acute GVHD and, in addition, lacrimal and salivary glands, mucous and serous membranes are also affected. The clinical picture resembles that of a number of collagen-vascular diseases. The incidence of chronic GVHD is higher in patients with previous acute GVHD and it increases with the patient age. Actual treatments involve the use of immunosuppressors and cytotoxic drugs. These approaches increase the risk of engraftment failures, delayed immune reconstitution, viral infections and relapses of the original malignant disease.
On the other hand, in vitro and in vivo immunosuppressive properties of bone marrow derived mesenchymal stem cells (BM-MSCs) have been reported. Said BM-MSCs are negative for the hematopoietic stem cell and endothelial CD34 marker antigen. The immunosuppressive properties of BM-MSCs strengthen the clinical relevance of said cells in allogenic transplantation by reducing the incidence and severity of GVHD [Jorgensen C. et al., (2003) Gene Therapy, 10, 928-931]. However, the use of BM-MSCs has a number of drawbacks such as they are obtained from a donor through an aggressive intervention that requires the general anaesthesia of the donor, sufficient BM-MSCs may not be obtained from some donors (particularly from older donors or those with malignant diseases), BM-MSCs are present in very low numbers in bone marrow, bone marrow aspirates are mostly dedicated to transplantation of haematopoietic stem cells, and BM-MSCs display a low in vitro proliferative potential, and, consequently, the generation of a therapeutically effective dose of said cells is relatively slow. Consequently, there is a need for an alternative source of mesenchymal cells for the treatment of GVHD.
The inventors have now found that adipose tissue derived mesenchymal stem cells can be used for the prevention and/or treatment of GVHD. Adipose tissue derived mesenchymal stem cells (AD-MSCs) are mesenchymal stem cells (MSCs) that can be obtained from adipose tissue, e.g., from aspirates of adipose tissue. A method for the isolation and ex vivo expansion of AD-MSCs is disclosed in PCT/EP2005/010811. This patent application also discloses the phenotypic characterization of the AD-MSCs cell population by cell surface markers profile determination. As it is the case for BM-MSCs, the disclosed AD-MSCs are characterized to be predominantly negative for the hematopoietic stem cell and the endothelial CD34 marker antigen. The use of said AD-MSCs for repairing and regenerating tissues is disclosed therein. Recently, some researchers claimed to have generated immunosuppressive mesenchymal stem cells termed ADAS cells (adipose tissue derived adult stem cells) which share immunomodulatory properties with BM-MSCs. The researchers suggest that, similar to BM-MSCs, the infusion of said ADAS cells could decrease GVDH in allogeneic bone marrow transplantation [Puissant B. et al., (2005) British Journal of Haematology, 129, 118-129]. Said ADAS cells are, however, different from BM-MSCs, and also from AD-MSCs. In fact, the authors point out that in contrast to BM-MSCs, ADAS cells used in the functional test were positive for the hematopoietic stem cell and endothelial CD34 marker antigen, although the CD34+ staining on ADAS cells decreased according to passages.